Phosphodiesterases (PDEs) are a family of enzymes encoded by 21 genes and subdivided into 11 distinct families according to structural and functional properties. These enzymes are hydrolases that metabolically inactivate widely occurring intracellular second messengers, 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP) by catalytic hydrolysis of the 3′-ester bond, forming the inactive 5′-monophosphate. These two messengers regulate a wide variety of biological processes, including pro-inflammatory mediator production and action, ion channel function, muscle contraction, learning, differentiation, apoptosis, lipogenesis, glycogenolysis, and gluconeogenesis. They do this by activation of protein kinase A (PKA) and protein kinase G (PKG), which in turn phosphorylate a wide variety of substrates including transcription factors and ion channels that regulate innumerable physiological responses. In neurons, this includes the activation of cAMP and cGMP-dependent kinases and subsequent phosphorylation of proteins involved in acute regulation of synaptic transmission as well as in neuronal differentiation and survival.
On the basis of substrate specificity, the PDE families can be divided into three groups: i) the cAMP-specific PDEs, which include PDE4, 7 and 8; ii) the cGMP-selective enzymes PDE5 and 9; and iii) the dual-substrate PDEs, PDE1, 2 and 3, as well as PDE10 and 11.
Furthermore, PDEs are expressed differentially throughout the organism, including the central nervous system. Different PDE isozymes therefore may play different physiological functions. Compounds that selectively inhibit PDE families or isozymes may display particular therapeutic activity, fewer side effects, or both.
PDE10a is highly expressed in the brain with the highest expression residing in the nAcc olfactory tubercle, striatum and spiny neurons. There is a high co-incidence of PDE10a, D2 and D1 expression in these areas. Antipsychotics normalize a dopamine-evoked cAMP decrease, i.e. agonists at Gs-coupled D1 receptors result in increased intracellular cAMP and antagonists of the Gi-coupled D2 receptor also elevate the intracellular cAMP.
Since PDE10a hydrolyzes cAMP and cGMP, it is to be expected that PDE10a inhibitors will increase intracellular levels of cAMP and cGMP, thereby mimicking dopamine transmission at D1 mediated synapses (D1 agonism) and decreasing dopamine transmission at D2 mediated synapses (D2 antagonism). Therefore, PDE10a inhibitors are expected to have antipsychotic and cognitive-improving properties and may provide benefits for the treatment of schizophrenia.
Besides being a potential treatment for psychiatric disorders, PDE10a inhibitors may also be beneficial for the treatment of metabolic diseases. Although PDE10a is predominantly expressed in the brain, it is also expressed in neuroendocrine tissues such as pancreatic islets, adrenal gland, pituitary gland, and in the neuronal ganglion throughout the intestine. Because cAMP is a major regulator of glucose-stimulated insulin secretion from pancreatic islet β cells, PDE10a inhibitors may enhance insulin secretion and reduce blood glucose levels. They may also potentiate the actions of GLP-1, GPR119 agonists and other Gs-coupled GPCR agonists which signal via increased cAMP and the protein kinase A pathway. In addition, PDE10a inhibitors may potentiate incretin effects such as β cell proliferation and survival. A peripherally restricted PDE10a inhibitor has been shown to enhance insulin secretion and reduce the glucose excursion in lean Wistar rats (Bioorg. Med. Chem. Lett. 17 (2007) 2869-2873).
Further validation that PDE10a inhibition may have beneficial effects on metabolism includes the phenotype of the PDE10a knockout mice (US Patent Appl. US2009/0162286 A1). These mice are resistant to weight gain on a high fat diet, without an appreciable change in food consumption, and the differences in weight between the PDE10a knockout and wild type mice are predominantly due to differences in adiposity and not lean mass. When compared to wild type mice, the PDE10a knockout mice have lower plasma insulin, triglycerides, non-esterified free fatty acids and leptin. Although there does not appear to be a difference in the glucose excursion between knockout and wild type mice on a chow diet, there is a reduction in the glucose excursion during an oral glucose tolerance test. Additionally, there was a slight increase in oxygen consumption. Furthermore, PDE10a inhibitor treatment in mice fed a high fat diet showed similar changes to those observed between wild type and PDE10a knockout mice. PDE10a inhibitor treated mice exhibited 6% weight loss during the 14 day study with little changes in food intake and slight increases in oxygen consumption. In addition, they exhibited improvements in the glucose excursion during an oral glucose tolerance test.
Taken together, these data suggest that PDE10a inhibitors may be beneficial for the treatment of type II diabetes and obesity with potentiation of glucose-stimulated insulin secretion and the potential for weight loss. Additivity and/or synergy may be expected between PDE10a inhibitors and DPPIV inhibitors, GLP-1 mimetics and GPR119 agonists. They may work well as monotherapy or in conjunction with common treatments of type II diabetes, such as metformin, SGLT2 inhibitors, PPAR gamma agonists and DPPIV inhibitors.
Therefore, there is a need in the art for PDE10a inhibitors that are useful for the treatment of a disease, syndrome, or condition in a mammal in which the disease, syndrome, or condition is affected by the inhibition of the PDE10a receptor, such as Type II diabetes. It has been suggested in the scientific literature that compounds that do not accumulate in the brain tissue may possess fewer potential CNS side effects. Therefore, it is an objective of the present invention to identify compounds of Formula (I) that do not accumulate in the brain tissue where they may exert CNS effects.